Guidelines on Urolithiasis

Transcription

1 Guidelines on Urolithiasis H.-G. Tiselius, D. Ackermann, P. Alken, C. Buck, P. Conort, M. Gallucci, T. Knoll European Association of Urology 2006

2 TABLE OF CONTENTS PAGE 1. Background References 6 2. Classification Categories of stone formers Specific risk factors for stone formation References 7 3. Diagnostic procedures Diagnostic imaging Allergy to contrast medium Metformin Reduced renal function 9 Risk factors for the development of reduced renal function 9 Dosage of iodine Untreated hyperthyroidism References Analysis of stone composition References Biochemical investigations Analytical work-up in the acute phase Analysis of urine in search for risk factors of stone formation Comments on the analytical work-up References Stone burden References Treatment of patients with renal colic Pain relief Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) Prevention of recurrent episodes of renal colic Effects of diclofenac on renal function References Indications for active stone removal References Active removal of stones in the kidney Extracorporeal shock wave lithotripsy (ESWL) for stone removal ESWL for removal of large renal stones Location of the stone mass Stone burden Composition and hardness of the stone References Percutaneous removal of renal stones Complications References Aspects on staghorn stone treatment and importance of stone burden ESWL Percutaneous nephrolithotomy (PNL) ESWL and PNL Percutaneous surgery versus ESWL for removal of renal stones References Open surgery for removal of renal stones Indications for open surgery Operative procedures References 34 2 UPDATE JUNE 2005

3 7.5 Chemolytic possibilities Infection stones Brushite stones Cystine stones Uric acid stones Calcium oxalate and ammonium urate stones References Recommendations for removal of renal stones Active removal of stones in the ureter ESWL for removal of ureteral stones References Retrograde manipulation of stones Stenting References Ureteroscopy for removal of ureteral stones Standard endoscopic technique Anaesthesia Assessment of different devices Ureteroscopes Disintegration devices Baskets Dilatation and stenting Clinical results Complications Conclusion References Should ESWL or ureteroscopy (URS) be used for stone removal? References Recommendations for active removal of ureteral stones: all sizes General recommendations and precautions for stone removal Infections Bleeding Pregnancy Pacemaker Hard stones Radiolucent stones References Complete or partial staghorn stones Managing special problems References Residual fragments References Steinstrasse References Preventive treatment in calcium stone disease General recommendations References Pharmacological agents in prevention of recurrent calcium stone formation Thiazides and thiazide-like agents Alkaline citrate Orthophosphate Magnesium Allopurinol 66 UPDATE JUNE

4 Cellulose phosphate Pyridoxine Recommendations References Pharmacological treatment of uric acid stone disease References Pharmacological treatment of cystine stone disease References Pharmacological treatment of infection stone disease References ACKNOWLEDGEMENTS ABBREVIATIONS USED IN THE TEXT APPENDICES 77 A1 Approximate stone surface area with known diameters of the stone 77 A2 Devices for endoscopic disintegration of stones 78 A3 References 78 4 UPDATE JUNE 2005

5 1. BACKGROUND Patients with urolithiasis constitute an important part of everyday urological practice. The optimal clinical management of this disease requires knowledge of the diagnostic procedures, the rational treatment of acute stone colic and the modern principles of stone removal. It is also essential to have a basic understanding of the aetiological factors of stone formation and how a metabolic risk evaluation should be carried out in order to provide a sound basis for appropriate recurrence preventive measures. During the past few decades, the whole field of treatment of patients with urolithiasis has been characterized by changes that are attributable to pronounced technical achievements, an increased understanding of the mechanisms of stone formation and advancements in pharmacological treatment of the various aspects of stone disease. The guidelines and recommendations given below are based on results presented in the modern literature. Some of the therapeutic principles are the result of evidence obtained from randomized or controlled studies, whereas other statements rely on a substantial clinical experience. According to the principles set by the European Association of Urology (EAU) Guidelines Office, the scientific basis for the various recommendations or statements has been classified in terms of level of evidence and grade of recommendation when appropriate. The criteria for level of evidence (LE) (Table 1) and grades of recommendation (GR) (Table 2) are shown below (1). The abbreviations LE and GR are used in the tables and recommendations given in these guidelines. Table 1: Level of evidence (LE) Level Type of evidence 1a Evidence obtained from meta-analysis of randomized trials 1b Evidence obtained from at least one randomized trial 2a Evidence obtained from one well-designed controlled study without randomization 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Table 2: Grade of recommendation (GR) Grade A B C Nature of recommendations Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial Based on well-conducted clinical studies, but without randomized clinical trials Made despite the absence of directly applicable clinical studies of good quality The various recommendations are supported by comments based on the most important relevant publications. It needs to be emphasized, however, that no attempt has been made to cover the literature completely, as such a step was beyond the possibilities of our work. When recommendations were formulated, we focused mainly on medical aspects, since discussing associated economic issues may be - due to the extensive geographical diversity and variability between the financial systems in the health care sector - beyond the scope of a European guideline document. We are very well aware of the different treatment and technical facilities available geographically, but our intention has been to highlight the alternatives that appear most convenient for the patient in terms of low invasiveness and risk of complications. This does not mean that other methods are not applicable. However, when a certain form of therapy is not recommended, this has been specifically stated. A number of tables throughout the text give an overview of the most appropriate methods for stone removal for different stone situations and stone compositions (tables 15, 16, 18, 19, 20, 22, 24 & 26). Numbers (1, 2, 3, 4, 5) have been allocated to the procedures according to the consensus reached. When two procedures were considered equally useful they have been given the same number. The first alternative always has the number 1. The current edition of Guidelines on Urolithiasis published here is an update of our previously published document (2,3). UPDATE JUNE

6 1.1 REFERENCES 1. US Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research, 1992, pp Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. In: EAU guidelines. Edition presented at the 16 th EAU Congress, Geneva, Switzerland 2001 (ISBN ) Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. Eur Urol 2001;40: CLASSIFICATION 2.1 Categories of stone formers A system for subgrouping stone-forming patients into different categories is shown in Table 3. These different categories are useful when making decisions regarding the need for metabolic evaluation and medical treatment (1,2,3). Table 3: Categories of stone formers Definition Category Infection stone INF NON-CALCIUM Uric acid/ammonium urate/sodium urate stone UR STONES Cystine stone CY First-time stone former without residual stone or fragments S o First-time stone former with residual stone or fragments S res CALCIUM STONES Recurrent stone former with mild disease and without residual stone(s) or fragments R mo Recurrent stone former with mild disease and with residual stone(s) or fragments R m-res Recurrent stone former with severe disease with or without residual stone(s) or fragments or with specific risk factors R s irrespective of otherwise defined category (Table 4) 2.2 Specific risk factors for stone formation Risk factors for stone formation are listed in Table 4. 6 UPDATE JUNE 2005

7 Table 4: Risk factors for recurrent stone formation Onset of disease early in life, i.e., below 25 years of age Stones containing brushite (calcium hydrogen phosphate; CaHPO 4.2H 2 O) Strong family history of stone formation Only one functioning kidney (only one kidney does not mean an increased risk of stone formation, but these patients should be particularly considered for measures to prevent stone recurrence) Diseases associated with stone formation hyperparathyroidism (HPT) renal tubular acidosis (RTA) (partial/complete) cystinuria primary hyperoxaluria jejunoileal bypass Crohn s disease intestinal resection malabsorptive conditions sarcoidosis hyperthyroidism Medication associated with stone formation calcium supplements vitamin D supplements acetazolamide ascorbic acid in megadoses (> 4 g/day) sulphonamides triamterene indinavir Anatomical abnormalities associated with stone formation tubular ectasia (medullary sponge kidney) pelvo-ureteral junction obstruction caliceal diverticulum, caliceal cyst ureteral stricture vesico-ureteral reflux horseshoe kidney ureterocele 2.3 REFERENCES 1. Tiselius HG. Etiology and investigation of stone disease. Curriculum in Urology. Eur Urol 1998;33: Tiselius HG. Epidemiology and medical management of stone disease. BJU Int 2003;91: Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. Eur Urol 2001;40: UPDATE JUNE

8 3. DIAGNOSTIC PROCEDURES 3.1 Diagnostic imaging Stone disease very often presents as an episode of acute stone colic. Patients with renal stone colic usually have characteristic loin pain, vomiting and mild fever, and they may have a history of stone disease. The clinical diagnosis should be supported by an appropriate imaging procedure. This will immediately help to decide if a conservative approach is justified or if another treatment should be considered. Imaging is imperative in patients with fever or a solitary kidney, and when the diagnosis of stone is in doubt. The diagnostic work-up of all patients with symptoms of urinary tract stones requires a reliable imaging technique (Table 5). In case of an acute stone colic, excretory urography (intravenous pyelography, IVP) has been established as a gold standard. During recent years, unenhanced helical computed tomography (CT) examinations have been introduced as a quick and contrast-free alternative (1,2,3). In randomized prospective studies, the specificity and sensitivity of this method for patients with acute flank pain was found to be similar to that obtained with urography (4,5-9). In selected cases, additional information regarding renal function may be obtained by combining CT with contrast infusion. One great advantage of CT is the demonstration of uric acid and xanthine stones, which are radiolucent on plain films. Another advantage is the ability of CT to detect alternative diagnoses (7,10). However, the advantage of a non-contrast imaging modality has to be balanced against the higher radiation dose given to the patient during CT investigation (3,5,11). An alternative and commonly applied method for evaluating patients with acute flank pain is a plain film of kidneys, ureters and bladder (KUB) combined with ultrasonography (US). There is a huge bulk of experience to show that these two methods are sufficient in a large proportion of patients for the diagnosis of a ureteral stone. Special examinations carried out in selected cases include retrograde pyelography, antegrade pyelography and scintigraphy. Table 5: Imaging modalities in the diagnostic work-up of patients with acute flank pain Examination GR and/or LE References Comment KUB + US B/2a Excretory urography Standard 3.1 Unenhanced helical CT A/ GR = grade of recommendation; LE = level of evidence; CT = computed tomography; KUB = kidney, ureters and bladder urography; US = ultrasound. Although the intravascular administration of contrast medium is usually a concern for the radiologist, contrast medium is occasionally used as an auxiliary procedure for stone localization during shock wave lithotripsy. Many urologists also take responsibility for the diagnostic radiological work-up of patients with stone problems. It is therefore essential to have a basic understanding of the risks associated with the use of contrast medium and the necessary precautions Allergy to contrast medium Where there is a need for administration of contrast medium to patients who have reported allergic reactions (Table 7), or in those who are at such a risk, the following precautions should be taken (12,13): Always use low-molecular non-ionic contrast medium. Give a corticosteroid (e.g., prednisolone 30 mg) between 12 and 2 hours before the contrast medium is injected. This medication might be combined with an intramuscular injection of an anti-histamine agent (e.g., clemastine 2 mg), given 1 hour before contrast administration Metformin Administration of metformin (a drug used to treat diabetes type II) might give rise to lactic acidosis in case of contrast-induced anuria (14-16). This is an unusual complication caused by retention of dimethylbiguanide. Unfortunately, lactic acidosis is associated with high mortality and great care needs to be taken when using contrast medium in patients taking metformin, particularly in the presence of reduced renal function (i.e., serum creatinine > 130 µmol/l). According to the recommendations given by the European Society of Urogenital Radiology (12,13) the serum creatinine level should be measured in every patient with diabetes being treated with metformin. In metformin-treated patients with a normal serum creatinine, contrast medium can be administered, but the intake of metformin should be stopped from the time of the radiological examination until 48 hours have passed and the serum creatinine remains normal. 8 UPDATE JUNE 2005

9 In patients with reduced renal function, medication with metformin should be stopped and administration of contrast medium delayed until 48 hours have passed after the last intake of metformin. Treatment with metformin may resume 48 hours after the examination provided that serum creatinine remains at the pre-examination level. In a situation where no information on renal function is available, alternative imaging techniques should be used. In a situation when contrast medium has been administered to a patient on metformin treatment, without information on the renal function, or with a reduced renal function, administration of metformin should be stopped immediately and the patient should be hydrated so that diuresis is > 100 ml/h during 24 hours. Serum creatinine, lactic acid and blood ph should be monitored. Symptoms of lactic acidosis are vomiting, somnolence, epigastric pain, anorexia, hyperpnoea, lethargy, diarrhoea and thirst. The investigative findings are a blood ph < 7.25 and serum lactic acid concentration > 5 mmol/l (14,16) Reduced renal function Intravenous administration of contrast medium can bring about a reduced renal perfusion and toxic effect on tubular cells. The vasoconstriction of glomerular afferent arterioles causes a reduced glomerular filtration rate (GFR) and an increased renal vascular resistance. Nephrotoxicity caused by contrast medium is diagnosed by the demonstration of a 25% or 44 µmol/l increase in serum creatinine during the 3 days that follow intravascular administration of the agent when there is no alternative explanation. Risk factors for the development of reduced renal function The following risk factors should be noted before intravenous contrast medium is used: increased serum creatinine dehydration age over 70 diabetes congestive heart failure concurrent treatment with nephrotoxic drugs, such as non-steroidal anti-inflammatory agents (NSAIDs) and aminoglycosides (the latter should be stopped for at least 24 hours). Patients with multiple myeloma should either be examined with an alternative method or after adequate hydration. Avoid repeated injections of contrast medium at intervals less than 48 (see section ) - 72 hours. Dosage of iodine Reduced renal function means that the serum creatinine > 140 µmol/l or that the GFR is < 70 ml/min. For a patient with a GFR of ml/min, the administered dose of iodine should not exceed g. When the GFR is reduced to a level between ml/min, the dose of iodine should be limited to the same amount as the GFR expressed in ml/min/1.73m 2 body surface area (12,13). Table 6 lists useful formulae for calculating GFR and body surface area (17). Table 6: Formulae for calculating glomerular filtration rate (GFR) and body surface area (17) Men: GFR = (140 - age) x kg/(0.82 x serum creatinine) Women: GFR = (0.85 x (140 - age) x kg/(0.82 x serum creatinine) For patients < 20 years, the following formula should be used: Creatinine clearance = (42.5 x height(cm)/serum creatinine) x (kg/70) 0.07 GFR = creatinine clearance x 1.73m 2 Body surface area = kg x height(cm) x In patients with a serum/plasma-creatinine level exceeding 140 µmol/l (1.6 mg/100 ml) hydration before and after the use of contrast medium may be beneficial in order to prevent nephropathy. The administration of N- acetylcysteine 600 mg twice on the day before contrast injection has been recommended to prevent renal failure caused by contrast medium (18). UPDATE JUNE

10 3.1.4 Untreated hyperthyroidism For patients in whom hyperthyroidism is suspected the TSH (thyroid stimulating hormone) level should be assessed before use of contrast medium. Contrast medium should not be given unless these patients are appropriately treated. Table 7: Considerations regarding excretory urography Contrast medium should not be given to, or LE Selected Comment avoided in the following circumstances references Patients with an allergy to contrast media - 12, When the serum or plasma creatinine level is > 150 µmol/l To patients on medication with metformin To patients with myelomatosis LE = level of evidence REFERENCES 1. Smith RC, Rosenfield AT, Choe KA, Essenmacher KR, Verga M, Glickman MG, Lange RC. Acute flank pain: Comparison of non-contrast-enhanced CT and intravenous urography. Radiol 1995;194: Smith RC, Verga M, McCarthy S, Rosenfield AT. Diagnosis of acute flank pain: value of unenhanced helical CT. Am J Roentgenol 1996;166: Kobayashi T, Nishizawa K, Watanabe J, Ogura K. Clinical characteristics of ureteral calculi detected by non-enhanced computerized tomography after unclear results of plain radiography and ultrasonography. J Urol 2003;170: Sudah M, Vanninen RL, Partanen K, Kainulainen S, Malinen A, Heino A, Ala-Opas M. Patients with acute flank pain: comparison of MR urography with unenhanced helical CT. Radiol 2002;223: Homer JA, Davies-Payne DL, Peddinti BS. Randomized prospective comparison of non-contrast enhanced helical computed tomography and intravenous urography in the diagnosis of acute ureteric colic. Aus Radiol 2001;45: Shokeir AA, Abdulmaaboud M. Prospective comparison of non-enhanced helical computerized tomography and Doppler ultrasonography for the diagnosis of renal colic. J Urol 2001;165: Gray Sears CL, Ward JF, Sears ST, Puckett MF, Kane CJ, Amling CL. Prospective comparison of computerized tomography and excretory urography in the initial evaluation of asymptomatic microhematuria. J Urol 2002;168: Miller OF, Rinner SK, Reichard SR, Buckley RG, Donovan MS, Graham IR, Goff WB, Kane CJ. Prospective comparison of unenhanced computed tomography and intravenous urogram in the evaluation of acute flank pain. Urology 1998;52: Dalrymple NC, Verga M, Anderson KR, Bove P, Covey AM, Rosenfield AT, Smith RC. The value of unenhanced helical computerized tomography in the management of acute flank pain. J Urol 1998;159: UPDATE JUNE 2005

11 10. Mindelzun RE, Jeffrey RB. Unenhanced helical CT evaluating acute abdominal pain: a little more cost, a lot more information. Radiol 1997;205: Shinokara K. Editorial: Choosing imaging modality in J Urol 2003;170: Morcos SK, Thomsen HS, Webb JA; Contrast Media Safety Committee of the European Society of Urogenital Radiolology. Prevention of generalized reactions to contrast media: a consensus report and guidelines. Eur Radiol 2001;11: Thomsen HS, Morcos SK. Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines. Br J Radiol 2003;76: Nawaz S, Cleveland T, Gaines PA, Chan P. Clinical risk associated with contrast angiography in metformine treated patients: a clinical review. Clin Radiol 1998;53: McCartney MM, Gilbert FJ, Murchinson LE, Pearson D, McHardy K, Murray AD. Metformin and contrast media - a dangerous combination? Clin Radiol 1999;54: Thompson NW, Thompson TJ, Love MH, Young MR. Drugs and intravenous contrast media. BJU Int 2000;85: &list_uids= Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: Tepel M, Van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographiccontrast-agent-induced reductions in renal function by acetylcysteine. N Eng J Med 2000;343: Analysis of stone composition Stones that pass spontaneously, are removed surgically, or excreted as fragments following disintegration, should be subjected to stone analysis to determine their composition (1-5). The preferred analytical procedures are X-ray crystallography and infrared spectroscopy. All patients should have at least one stone analyzed. Repeated analysis is indicated when any changes in urine composition, due to medical treatment, dietary habits, environment or diseases, can be expected to have influenced the stone composition. When stone(s) or stone material have not been retrieved, conclusions on stone composition may be based on the following observations: Qualitative cystine test (e.g., sodium nitroprusside test, Brand s test (6), or any other cystine test). Bacteriuria/urine culture (in the case of a positive culture, ask for urease-producing microorganisms). Demonstration of crystals of struvite or cystine upon microscopic examination of the urinary sediment. Serum urate (in cases where a uric acid or urate stone is a possible alternative). Urine ph (low in patients with uric acid stones, high in patients with infection stones). Radiographical characteristics of the stone. An appropriate quantitative or semi-quantitative analysis of the stone material should enable conclusions to be drawn regarding the main constituent or constituents. UPDATE JUNE

12 The following calcium stones not associated with infection are referred to as radio-opaque stones: Calcium oxalate calcium oxalate monohydrate calcium oxalate dihydrate Calcium phosphate hydroxyapatite carbonate apatite octacalcium phosphate brushite whitlockite. The following stones not associated with infection are referred to as uric acid/urate stones: Uric acid Ammonium urate Sodium urate. Infection stones have the following typical constituents: Magnesium ammonium phosphate Carbonate apatite. Less common stone constituents include 2,8-dihydroxyadenine, xanthine and various drug metabolites (e.g., sulphonamide, indinavir). Calcium stones, uric acid/urate stones and cystine stones associated with infection are referred to as stones with infection REFERENCES 1. Asper R. Stone analysis. Urol Res 1990;18(Suppl): Herring LC. Observations on the analysis of ten thousand urinary calculi. J Urol 1962; dopt= 3. Daudon M, Jungers P. Clinical value of crystalluria and quantitative morphoconstitutional analysis of urinary calculi. Nephron Physiol. 2004;98: Otnes B. Crystalline composition of urinary stones in Norwegian patients. Scand J Urol Nephrol 1983;17: Leusmann DB, Blaschke R, Schwandt W. Results of 5,035 stone analyses: a contribution to epidemiology of urinary stone disease. Scand J Urol Nephrol 1990;24: Brand E, Harris MH, Biloon S. Cystinuria: Excretion of cystine complex which decomposes in the urine with the liberation of cystine. J Clin Chem 1980;86: Biochemical investigations Analytical work-up in the acute phase For patients with an acute stone episode, the routine laboratory investigations should include: Urinary sediment/dipstick test for demonstration of red cells. White cells and bacteria (nitrite). Approximate ph level. Serum creatinine should be analyzed as a measure of the renal function. In cases of fever, C-reactive protein (CRP) should be assessed, and a blood white cell count and urine culture carried out. 12 UPDATE JUNE 2005

13 In cases of vomiting, serum sodium and serum potassium levels should be measured. In order to avoid the need for future repeated blood analyses in the search for metabolic risk factors, it might be helpful to assess levels of serum calcium and serum urate at this point in time Analysis of urine in search for risk factors of stone formation For an identification of metabolic risk factors of stone formation, an analytical programme for the different categories of stone formers is shown in Table 9. Two urine collections for each set of analyses are recommended. The urine collections are repeated when necessary (1-3). A number of alternative collection options are feasible, with a few examples listed in Table 8. Table 8: Options for urine collection Option 1 Two 24-hour collections Sample 1 collected in a bottle containing 30 ml of 6 mol/l hydrochloric acid Sample 2 collected in a bottle containing 30 ml of 0.3 mol/l sodium azide Option 2 One 24-hour collection Sample collected in a bottle containing 30 ml of 6 mol/l hydrochloric acid Option 3 One 16-hour urine collection Sample 1 collected between and hours in a bottle and one 8-hour urine collection containing 20 ml of 6 mol/l hydrochloric acid Sample 2 collected between and hours in a bottle containing 10 ml of 0.3 mol/l sodium azide Option 4 Spot urine sample The excretion of each urine variable is related to the creatinine level The presence of hydrochloric acid (HCl) prevents the precipitation of calcium oxalate and calcium phosphate in the container during storage. HCl also counteracts the oxidation of ascorbate to oxalate. In acidified samples, uric acid precipitates and has to be dissolved by alkalinization if urate excretion is of interest. Urate can be analyzed in samples collected with sodium azide. A collection of urine without HCl is necessary for ph measurement. In this respect, a sample collected with sodium azide is useful. A night-time urine sample in which ph is measured soon after the urine has been collected is useful because the ph may be altered when urine is stored. Table 9: Analytical programme for patients with stone disease Category Blood analysis Urine analysis Prevention (serum / plasma) Follow-up INF Creatinine Culture, ph Yes UR Creatinine, Urate Urate, ph Yes CY Creatinine Cystine, ph Yes So Yes (see Table 10) Limited urine analysis No (only fasting spot urine) Sres Yes (see Table 11) Yes (see Table 11) Yes Rmo Yes (see Table 10) Limited urine analysis No (only fasting spot urine) Rm-res Yes (see Table 11) Yes (see Table 11) Yes Rs Yes (see Table 11) Yes (see Table 11) Yes A patient with uncomplicated stone disease is one who is either stone-free after the first stone episode or who has a history of mild recurrent disease with long intervals between stone episodes (categories S o, R mo ; Table 3). The stone, blood (serum, plasma) and urine analyses recommended for such patients are shown in Table 10. UPDATE JUNE

14 Table 10: Blood and urine investigations required for analysis of risk factors in patients with uncomplicated stone disease Stone analysis Blood analysis Urine analysis In every patient one stone should be analyzed Calcium Fasting morning spot urine Albumin 1 sample, dipstick test for: Creatinine ph Urate 2 Leucocytes/bacteria 3 Cystine test 4 1 Either analysis of calcium + albumin to correct for differences in calcium concentration attributable to the albumin binding or direct analysis of ionized (free) calcium. 2 Optional analysis, helpful in suspected uric acid/urate stone disease. 3 Urine culture in case of bacteriuria. 4 Cystine test if cystinuria cannot be, or has not been, excluded by other means. A patient with complicated stone disease has a history of frequent recurrences, with or without residual fragments or stones in the kidney or specific risk factors. First-time stone formers with residual fragments may also be considered in this respect (categories: R s, S res, R m-res ; Table 3). The stone, blood and urine analyses recommended for these patients are shown in Table 11 (4-12). Urine collection should be postponed until at least 4 weeks have passed after stone removal or after an episode of obstruction and should never be carried out in the presence of infection or haematuria. Special tests that may be required are shown in Table 12 (13-18). Table 11: Analysis in patients with complicated stone disease Stone analysis Blood analysis Urine analysis In every patient one stone should be analyzed Calcium Fasting morning spot urine sample: Albumin 1 Dipstick test Creatinine ph Urate 2 Leucocytes/bacteria 3 Cystine test 4 Urine collection during a defined period of time: Calcium Oxalate Citrate Urate 6 Magnesium 2,4 Phosphate 2,4,5 Urea 2,5 Sodium 2,5 Potassium 2,5 Creatinine Volume 1 Either analysis of calcium + albumin to correct for differences in calcium concentration attributable to the albumin binding, or direct analysis of ionized (free) calcium. 2 Optional analysis hour urine, 16-hour + 8-hour urine or any other collection period can be chosen provided normal excretion data are available (4-7). A spot urine sample can be used with creatinine-related variables (7). 4 Analysis of magnesium and phosphate is necessary to calculate estimates of supersaturation with calcium oxalate (CaOx) and calcium phosphate (CaP), such as AP(CaOx) index and AP(CaP) index (8-12). 5 Urea, phosphate, sodium and potassium measurements are used to assess the dietary habits of the patient. 6 As uric acid precipitates in acid solutions, urate has to be analyzed in a sample that has not been acidified or following alkalinization to dissolve uric acid. When a 16-hour urine sample has been collected in a bottle with an acid preservative, the remaining 8 hours of the 24-hour period can be used to collect urine with sodium azide for analysis of urate. 14 UPDATE JUNE 2005

15 3.3.3 Comments on the analytical work-up The purpose of analyzing serum or plasma calcium is to identify patients with hyperparathyroidism (HPT) or other conditions associated with hypercalcaemia. In the case of a high calcium concentration (> 2.60 mmol/l), the diagnosis of HPT should be established or excluded by repeated calcium analyses and assessment of the parathyroid hormone level (19-24). In those patients in whom a stone analysis has not been carried out, a high serum urate level together with a radiolucent stone support the suspicion of a uric acid stone. In this regard it needs to be emphasized that whereas a uric acid stone is usually invisible on a plain film (KUB), it is clearly demonstrated with a CT examination. A fasting morning urine sample (or a spot morning urine sample) should be used to measure ph (25). A ph above 5.8 in fasting morning urine raises the suspicion of incomplete or complete renal tubular acidosis (RTA) (26). In the same fasting morning or spot urine sample, bacteriuria and cystinuria can be excluded or confirmed by an appropriate test (27). The aim of adding serum potassium to the analytical programme is to obtain further support for a diagnosis of suspected RTA. Hypokalaemic hypocitraturia may be one reason for therapeutic failures in patients treated with thiazides. The recommendation to collect two urine samples is based on observations that such an approach will increase the likelihood of detecting urine abnormalities. Various collection periods, such as for 24 hours, 16 hours, 17 hours, 12 hours, 4 hours or even spot urine samples, are useful for this purpose provided a set of normal values is available for the collection period (4-7). It must be emphasized that the urine sample used for analysis of calcium, oxalate, citrate and phosphate has to be acidified, preferably with HCl. The reasons for this acidification are: To maintain calcium, oxalate and phosphate in solution, during and after the collection period. To prevent bacterial growth and the associated alteration of urine composition. To prevent the in-vitro oxidation of ascorbate to oxalate (28,29). The following urine variables can be analyzed in the acidified sample: calcium, oxalate, citrate, magnesium, phosphate, urea, sodium, chloride and potassium. Although the creatinine concentration might be slightly affected, it has to be assessed in the same sample when creatinine-related variables are used and also for conclusions on the completeness of the collection. Urate forms uric acid in the acidified urine and has to be analyzed either following complete dissolution with alkali or in a urine sample that has not been acidified. The optional analysis of urea, phosphate and sodium helps to reflect dietary factors of therapeutic significance. The protein intake can be derived from the urea excretion (U urea, mmol/l) and urine volume in litres (V) as follows (30): Intake of protein (gram) during the 24h period = (U urea x 0.18) + 13 Estimates of the ion-activity products of calcium oxalate (AP[CaOx] index) and calcium phosphate (AP[CaP] index) can be calculated as follows (31-37): AP[CaOx] index = 1.9 x Ca 0.84 x Ox x Cit x Mg x V In this formula, the urine volume (V) is expressed in litres and the urine variables (Ca, calcium; Ox, oxalate; Cit, citrate; Mg, magnesium) in mmol excreted during the collection period. The factor 1.9 is specific for the 24-hour period. For a 16-hour urine sample, this factor is 2.3. For other collection periods, the reader should consult reference 5. The AP[CaOx] index approximately corresponds to 10 8 x AP CaOx (where AP CaOx is the ion-activity product of calcium oxalate). The AP[CaP] index for a 24-hour urine sample is calculated in the following way: AP[CaP] index = 2.7 x 10-3 x Ca 1.07 x P 0.70 x (ph - 4.5) 6.8 x Cit x V The AP[CaP] index approximately corresponds to x AP CaP (where AP CaP is the ion-activity product of calcium phosphate). Factors for other collection periods can be found in reference 5. A relationship between abnormalities in urine composition and severity of calcium stone formation has been demonstrated (38-44). It should be noted that although individual abnormal urine variables might indicate a risk of stone formation, it is the concerted action of the various urine constituents which result in supersaturation and crystallization of the stone. The additional analytical work-up in patients with calcium stone disease is summarized in Table 12. It might occasionally be useful to carry out a calcium loading test, but this test is not often used clinically today (13). UPDATE JUNE

16 Table 12: Additional analytical work-up in patients with calcium stone disease ph profile (13) Repeated measurements of ph during the 24-hour period Frequent samples should be collected for immediate measurement of ph with ph paper or a glass electrode. Sampling every second hour or otherwise as appropriate. Acid loading (14-18) This test is carried out together with blood sampling to show whether or not the patient has a complete or an incomplete acidification defect: Breakfast + NH 4 Cl tablets (0.1 g/kg body weight), drink 150 ml Collect urine and measure ph, drink 150 ml Collect urine and measure ph, drink 150 ml Collect urine and measure ph, drink 150 ml Collect urine and measure ph, drink 150 ml Collect urine and measure ph, lunch Interpretation: a ph of 5.4 or lower indicates no RTA Findings in blood Complete RTA Incomplete RTA ph Low Normal Bicarbonate Low Normal Potassium Low Normal Chloride High Normal NH 4 Cl = ammonium chloride; RTA = renal tubular acidosis REFERENCES 1. Hobarth K, Hofbauer J, Szabo N. Value of repeated analysis of 24-hour urine in recurrent calcium urolithiasis. Urology 1994;44: &itool=iconabstr 2. Hess B, Hasler-Strub U, Ackermann D, Jaeger PH. Metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasis. Nephrol dial transplant 1997;12: &itool=iconfft 3. Bek-Jensen H, Tiselius HG. Repeated urine analysis in patients with calcium stone disease. Eur Urol 1998;33: &itool=iconabstr 4. Berg C, Larsson L, Tiselius HG. The composition of four-hour urine samples from patients with calcium oxalate stone disease. Br J Urol 1987;60: &itool=iconabstr 5. Tiselius HG. Solution chemistry of supersaturation. In: Kidney stones: medical and surgical management. Coe FL, Favus MJ, Pak CYC, Parks HG, Preminger GM (eds). Lippincott-Raven Publishers, Philadelphia:1996, pp Bek-Jensen H, Tiselius HG. Evaluation of urine composition and calcium salt crystallization properties in standardized 12-h night urine from normal subjects and calcium stone formers. Urol Res 1997; 25: &itool=iconabstr 7. Strohmaier WL, Hoelz K-J, Bichler KH. Spot urine samples for the metabolic evaluation of urolithiasis patients. Eur Urol 1997;32: &itool=iconabstr 8. Tiselius HG. An improved method for the routine biochemical evaluation of patients with recurrent calcium oxalate stone disease. Clin Chim Acta 1982;122: &itool=iconabstr 16 UPDATE JUNE 2005

17 9. Tiselius HG. A simplified estimate of the ion-activity product of calcium phosphate in urine. Eur Urol 1984;10: &itool=iconabstr 10. Tiselius HG. Aspects on estimation of risk of calcium oxalate crystallization in urine. Urol Int 1991;47: &itool=iconabstr 11. Tiselius HG. Risk formulas in calcium oxalate urolithiasis. World J Urol 1997;15: &itool=iconabstr 12. Tiselius HG. Metabolic evaluation of patients with urolithiasis. Urol Int 1997;59: &itool=iconnoabstr 13. Hesse A, Tiselius HG. Jahnen A (eds). In: Urinary stones - diagnosis, treatment and prevention of recurrence. Karger: New York, 1996, pp Backman U, Danielson BG, Johansson G, Ljunghall S, Wikström B. Incidence and clinical importance of renal tubular defects in recurrent renal stone formers. Nephron 1980;25: &itool=iconabstr 15. Knispel HH, Fitzner R, Kaiser M, Butz M. Acute acid load in recurrent oxalate stone formers. Urol Int 1988;43: &itool=iconabstr 16. Nutahara K, Higashihara E, Ishiii Y, Niijima T. Renal hypercalciuria and acidification defect in kidney stone patients. J Urol 1989;141: &itool=iconabstr 17. Osther PJ, Hansen AB, Rohl HF. Screening renal stone formers for distal renal tubular acidosis. Br J Urol 1989;63: Buckalew VM Jr. Nephrolithiasis in renal tubular acidosis. J Urol 1989;141: Halabe A, Sutton RA. Primary hyperparathyroidism and idiopathic hypercalciuria. Miner Electrolyte Metab 1987;13: Fuss M, Pepersack T, Corvilain J, Vandewalle JC, Van Geertruyden J, Simon J, Kinnaert P. Infrequency of primary hyperparathyroidism in renal stone formers. Br J Urol 1988;62: = 21. Broadus AE. Primary hyperparathyroidism. J Urol 1989;141: dopt= 22. Thomas WC Jr. Urinary calculi in hypercalcemic states. Endocrinol Metab Clin North Am 1990; 19: dopt= 23. Rose GA. Primary hyperparathyroidism. In: Renal tract stone. Wickham JEA, Buck AC (eds). Churchill Livingstone: Edinburgh,1990, pp Alvarez-Arroyo MV, Traba ML, Rapado A, de la Piedra C. Role of citric acid in primary hyperparathyroidism with renal lithiasis. Urol Res 1992;20: dopt= 25. Elliot JS, Sharp RF, Lewis L. Urinary ph. J Urol 1959; 81: dopt= UPDATE JUNE

18 26. Chafe L, Gault MH. First morning urine ph in the diagnosis on renal tubular acidosis with nephrolithiasis. Clin Nephrol 1994;41: dopt= 27. Brand E, Harris MM, Bildon S. Cystinuria: excretion of a cystine complex which decomposes in the urine with the liberation of free cystine. J Biol Chem 1930;86: Brown JM, Chalmers AH, Coxley DM, McWhinney BC. Enteric hyperoxaluria and urolithiasis. N Engl J Med 1986;32: and 1986;315: Wandzilak TR, D Andre SD, Davis PA, Williams HE. Effect of high dose vitamin C on urinary oxalate levels. J Urol 1994;151: Mitch WE, Walser M. Nutritional therapy of the uremic patient. In: The kidney. 3rd ed. Brenner BM, Rector FC Jr (eds). Saunders: Philadelphia, 1986, Vol II, pp Eisenberger F, Bub P, Schmidt A. The fate of residual fragments after extracorporeal shock wave lithotripsy. J Endourol 1992;6: Liedl B, Jocham D, Schuster C, Lunz C. Long-term results in ESWL-treated urinary stone patients.. Urol Res 1988;16: Cicerello E, Merlo F, Gambaro G, Maccatrozzo L, Fandella A, Baggio B, Anselmo G. Effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolithiasis patients. J Urol 1994;151: Fine JK, Pak YC, Preminger GM. Effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. J Urol 1995;153: Streem SB, Yost A, Mascha E. Clinical implications of clinically insignificant stone fragments after extracorporeal shock wave lithotripsy. J Urol 1996;155: Zanetti G, Seveso M, Montanari E, Guarneri A, Del Nero A, Nespoli R, Trinchieri A. Renal stone fragments following shock wave lithotripsy. J Urol 1997;158: Pacik D, Hanak T, Kumstat P, Turjanica M, Jelinek P, Kladensky J. Effectiveness of ESWL for lowerpole caliceal nephrolithiasis: evaluation of 452 cases. J Endourol 1997;11: Tiselius HG. Factors influencing the course of calcium oxalate stone disease. Eur Urol 1999;36: &query_hl=1 39. Robertson WG. A risk factor model of stone formation. Front Biosci 2003;8: &query_hl=3 40. Strauss AL, Coe FL, Deutsch L, Parks JH. Factors that predict the relapse of calcium nephrolithiasis during treatment. A prospective study. Am J Med 1982;72: &query_hl=5 41. Hsu TH, Streem SB. Metabolic abnormalities in patients with caliceal diverticular calculi. J Urol 1998; 160: &query_hl=7 42. Daudon M, Hennequin C, Boujelben G, Lacour B, Jungers P. Serial crystalluria determination and the risk of recurrence in calcium stone formers. Kidney Int 2005;67: &query_hl=10 18 UPDATE JUNE 2005

19 43. Tiselius HG, Bek-Jensen H, Fornander AM, Nilsson MA. Crystallization properties in urine from calcium oxalate stone formers. J Urol 1995;154: &query_hl= Raj GV, Auge BK, Assimos D, Preminger GM. Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys. J Endourol 2004;18: &query_hl=15 4. STONE BURDEN The size of a concrement (stone burden) can be expressed in different ways. A notation of the largest diameter is the most common way of expressing size in the literature, i.e., the length of the stone as measured on the plain film. With knowledge of the length (l) and the width (w), an appropriate estimate of the stone surface area (SA) can be obtained for most stones (1): SA = l x w x π x 0.25 For a quick estimate of the stone surface area, please refer to Table A1 (Appendix). The surface area can also be measured using computerized systems and from CT scans, but these are not always easy procedures. With knowledge of the surface area, the stone volume can be calculated by the formula below (2): Volume = 0.6 x SA 1.27 In this guideline document, we have based our recommendations on the stone surface area as well as on the largest stone diameter. 4.1 REFERENCES 1. Tiselius HG, Andersson A. Stone burden in an average Swedish population of stone formers requiring active stone removal: how can the stone size be estimated in the clinical routine? Eur Urol 2003; 43: Ackermann D, Griffith DP, Dunthorn M, Newman RC, Finlayson B. Calculation of stone volume and urinary stone staging with computer assistance. J Endourol 1989;3: TREATMENT OF PATIENTS WITH RENAL COLIC 5.1 Pain relief The relief of pain is usually the most urgent therapeutic step in patients with an acute stone episode. Pain relief involves the administration of the following agents by various routes: Diclofenac sodium (LE: 1b) Indomethacin Ibuprophen Hydromorphone hydrochloride + atropine sulphate Methamizol Pentazocine Tramadol Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) A double-blind study comparing diclofenac and spasmofen (a narcotic analgesic) (1) demonstrated a better effect with diclofenac and fewer side effects. In another double-blind, placebo-controlled study, the efficacy of diclofenac (2) was clearly demonstrated. UPDATE JUNE